U.S. patent number 5,626,871 [Application Number 08/193,141] was granted by the patent office on 1997-05-06 for preparation for intratracheobronchial administration.
This patent grant is currently assigned to Teijin Limited. Invention is credited to Hideki Kobayashi, Yuji Makino, Yoshiki Suzuki.
United States Patent |
5,626,871 |
Makino , et al. |
May 6, 1997 |
Preparation for intratracheobronchial administration
Abstract
A preparation for intratracheobronchial administration
comprising a powder preparation for intratracheobronchial
administration contained in a receptacle composed essentially of
hydroxypropyl methyl cellulose.
Inventors: |
Makino; Yuji (Hino,
JP), Kobayashi; Hideki (Hino, JP), Suzuki;
Yoshiki (Hino, JP) |
Assignee: |
Teijin Limited (Osaka,
JP)
|
Family
ID: |
15564710 |
Appl.
No.: |
08/193,141 |
Filed: |
February 14, 1994 |
PCT
Filed: |
June 11, 1993 |
PCT No.: |
PCT/JP93/00785 |
371
Date: |
February 14, 1994 |
102(e)
Date: |
February 14, 1994 |
PCT
Pub. No.: |
WO93/25193 |
PCT
Pub. Date: |
December 23, 1993 |
Foreign Application Priority Data
|
|
|
|
|
Jun 12, 1992 [JP] |
|
|
4-153538 |
|
Current U.S.
Class: |
424/451;
424/499 |
Current CPC
Class: |
A61K
9/0075 (20130101); A61K 9/4816 (20130101) |
Current International
Class: |
A61K
9/48 (20060101); A61K 009/48 (); A61K 009/72 ();
A61K 009/14 () |
Field of
Search: |
;424/451,499 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
59-34267 |
|
Feb 1984 |
|
JP |
|
61-100519 |
|
May 1986 |
|
JP |
|
Primary Examiner: Krass; Frederick
Attorney, Agent or Firm: Sughrue, Mion, Zinn, Macpeak &
Seas
Claims
We claim:
1. A preparation for intratracheobronchial administration
comprising a powder preparation for intratracheobronchial
administration contained in a receptacle comprising at least one
component selected from the group consisting of hydroxypropyl
methyl cellulose, methyl cellulose, hydroxypropyl cellulose,
starch, hydroxypropyl starch, and sodium alignate, wherein the
amount of said component is at least 80% by weight of said
receptacle, and wherein at least 80% by weight of the particles in
said powder preparation, based on the weight of said preparation,
have a diameter ranging from about 0.5 to 149 .mu.m.
2. A preparation for intratracheobronchial administration as
claimed in claim 1, wherein said component is hydroxypropyl methyl
cellulose.
3. A preparation for intratracheobronchial administration as
claimed in claim 1, wherein said receptacle is molded so as to
charged as a unit dose or a multidose in an administering utensil
for intratracheobronchial administration of powder.
4. A preparation for intratracheobronchial administration as
claimed in claim 3, wherein said receptacle is charged as a unit
dose in the administering utensil for intratracheobronchial
administration of powder, which is a medical hard capsule.
5. A preparation for intratracheobronchial administration as
claimed in claim 1, wherein said receptacle is integrated with an
administering utensil for intratracheobronchial administration of
said powder, and is disposable.
6. A preparation for intratracheobronchial administration as
claimed in any one of claims 1 or 2-5, wherein said powder
preparation for intratracheobronchial administration is a powder
preparation which is inhaled through a nasal cavity and deposited
in the nasal cavity.
7. A preparation for intratracheobronchial administration as
claimed in any one of claims 1 or 2-5, wherein said powder
preparation for intratracheobronchial administration is a powder
preparation which is sprayed into a nasal cavity and deposited in
the nasal cavity.
8. A preparation for intratracheobronchial administration as
claimed in any one of claims 1 or 2-5, wherein said powder
preparation for intratracheobronchial administration is a powder
preparation which is inhaled through an oral cavity and deposited
in the oral cavity, pharynx, larynx, trachea, bronchi, bronchioles,
or alveoli.
9. A preparation for intratracheobronchial administration as
claimed in any one of claims 1 or 2-5, wherein said powder
preparation for intratracheobronchial administration is a powder
preparation which is sprayed into a oral cavity and deposited in
the oral cavity, pharynx, larynx, trachea, bronchi, bronchioles, or
alveoli.
10. A preparation for intratracheobronchial administration as
claimed in any one of claims 1 or 2-5, wherein said powder
preparation for intratracheobronchial administration is that
comprising a medicament selected from the group consisting of
antiallergic drugs, steroidal antiinflammatory drugs, non-steroidal
antiinflammatory drugs, enzymatic antiinflammatory drugs,
antihistamines, antibiotics, germicides, chemotherapeutic drugs,
elastase inhibitors, local anesthetics, vasoconstrictors, cardiacs,
vasodilators, anti-malignant-tumor drugs, sympathomimetic drugs,
sympatholytic drugs, parasympatholytic drugs, sputum solubilizers,
mucosa lubricants, peptides, proteins, and vaccines.
11. A preparation for intratracheobronchial administration as
claimed in claim 10, wherein said powder preparation for
intratracheobronchial administration further comprises a
pharmaceutical vehicle to be administered simultaneously with said
medicament, said pharmaceutical vehicle being selected from the
group consisting of cellulose ethers; water absorbable and slightly
water soluble celluloses, water absorbable and slightly water
soluble proteins; water absorbable and slightly water soluble gums;
water absorbable and slightly water soluble cross-linked vinyl
polymers; sugars; and amino acids.
12. The preparation for intratracheobronchial administration as
claimed in any one of claims 1 or 2-5, wherein said powder
preparation for intratracheobronchial administration is that
comprising a medicament selected from the group consisting of
steroidal antiinflammatory drugs, sympathomimetic drugs,
parasympatholytic drugs, peptides and proteins.
13. The powder preparation for intratracheobronchial administration
as claimed in claim 12, wherein said powder preparation for
intratracheobronchial administration further comprises a
pharamaceutical vehicle to be administration simultaneously with
said medicament, wherein said pharmaceutical vehicle is selected
from the group consisting of water absorbable and slightly water
soluble celluloses; water absorbable and slightly water soluble
starches; water absorbable and slightly water soluble proteins;
water absorbable and slightly water soluble gums; and water
absorbable and slightly water soluble cross-linked vinyl polymers.
Description
TECHNICAL FIELD
The present invention relates to a preparation for
intratracheobronchial administration. More specifically, the
present invention relates to a preparation for
intratracheobronchial administration, comprising a powder
preparation for intratracheobronchial administration contained in a
receptacle composed of at least one component selected from the
group consisting of hydroxypropyl methyl cellulose, methyl
cellulose, hydroxypropyl cellulose, starches, hydroxypropyl
starches, and sodium alginate. Furthermore, specifically, the
present invention is concerned with a preparation for
intratracheobronchial administration, contained in a receptacle, in
which a medicament in the powder preparation for
intratracheobronchial administration is contained in the receptacle
composed of at least one component of cellulose
derivatives-analogues, that is, selected from the group consisting
of hydroxypropyl methyl celluloses, methyl celluloses,
hydroxypropyl celluloses, starches, hydroxypropyl starches, and
sodium alginate, and the medicament is not easily adhered to the
receptacle so that the amount of the intratracheobronchially
delivered medicament is improved.
BACKGROUND ART
The airway extending from the nasal cavity, oral cavity to the
pharynx, larynx, trachea, bronchia, bronchioles, and alveoli is a
passageway for expiratory and inspiratory air.
In the airway, there occur many diseases such as nasal allergies,
asthma, bronchitis, lung emphysema, and the like. The method for
administering a medicament in the pharmacotherapy for these
diseases may be classified into the whole body administration such
as the use of orally administered medicaments and injections, and
intratracheobronchial local administration such as the use of
nebulas, inhalants, and the like.
Oral administration is an easy method, and the use of injections
ensures the absorption of the injections into the body, and
therefore, these administering methods have widely been employed.
However, intratracheobronchial administration of a medicament is
highly valuable in the light of convergence of the medicament into
an acting site, reduction of adverse side effects due to the
convergence, and fast-acting properties of the effect of the
medicament.
Further, in addition to the local administration of a medicament
for such diseases as mentioned above, which occur in the airway,
there has recently been a trial of proceeding a medicament from
alveoli to blood by utilization of the fact that the barrier
between the alveoli and blood is dwarfish, and the
intratracheobronchial administration has now attracted public
attention as a systemic administration method for peptides,
proteins or the like, which are metabolized in the gastrointestinal
tract, liver or the like so as to be inactivated, when these are
orally administered.
In addition, there have been attempts to locally administer a
vaccine in the airway by utilizing the antigen recognizing function
of the lymphatic system in the airway, so as to prevent and treat a
disease. Therefore, it may be said that the importance of
intratracheobronchial administration is very significant.
The preparations for intratracheobronchial administration to be
used for the above intratracheobronchially administering method can
be classified into the following two kinds, with respect to the
properties of the particles of the preparations: (1) preparations,
the droplets of which are deposited to the inside of the airway,
and (2) preparations, the fine solid particles of which are
deposited to the inside of the airway.
A preparation (1) is usually an aqueous solution containing a
medicament, which is atomized by a nebulizer, and inhaled into the
airway as minute droplets. Preparations (2) are further roughly
classified into (i) aerosol preparations, in which the fine solid
particles are contained in a pressure container in a state such
that they are dispersed in a fluorohydrocarbon, and when they are
discharged out of the vessel in the case of the use thereof, these
particles move in the airway together with the fluorohydrocarbon,
and after the fluorohydrocarbon has rapidly evaporated, they are
finally deposited in the airway, as fine solid particles of the
medicaments, and (ii) powder preparations in which a medicament is
contained as fine solid particles in receptacle, and in the case of
using any of them, the fine solid particles of the medicament are
inhaled into the airway directly from the container or by use of an
administration utensil, by injection or inhalation of breath, and
deposited to the inside of the airway as fine solid particles of
the medicament.
These preparations have already been put to practical use,
regarding all the types thereof. The liquid preparations of (1)
require a nebulizer or atomizer and are therefore, not convenient
to carry. The fluorohydrocarbon aerosol preparations of (2)-(i) are
simple to handle, and have been widely used, but there has arisen a
trend of public opinion to restrict the use of these preparations,
considering the problem of air pollution from fluorohydrocarbon
gases. Under such circumstances, powder preparations for
intratracheobronchial administration of (2)-(ii), which have
remained comparatively backward in the development as compared with
the other two kinds of preparations, have come to noticeably
attract public attention.
In order to administer a powder preparation for
intratracheobronchial administration, a receptacle for the powder
preparation and an administering utensil are needed. In the
following, the "receptacle" means a receptacle in which the powder
preparation is directly contained, and the powder preparation is
contained in the receptacle, after it has been prepared by mixing
and stored until it is used. Therefore, the receptacle is
ordinarily tightly sealed. In addition, the administering utensil
in the present invention is generally a device for taking the
powder preparation out of the above-mentioned receptacles
containing the powder preparation in such a state as can be
administered into the airway; it is, e.g., a device for maintaining
the tightly sealed powder preparation at a proper position, and
boring a hole in the receptacle so as to enable the powder
preparation to proceed into the airway. The receptacle and
administering utensil are usually separately produced, but they may
be produced as an integrated product. For example, a part of a
receptacle is removed when using the powder preparation, so as to
produce a hole, whereby it becomes possible to cause the powder
preparation contained in the receptacle to move into the
respiratory tract from the receptacle.
The powder preparation, which has been made movable into the airway
from the receptacle by use of an administering utensil or by
performing some operations in an integrated product of a receptacle
and administering utensil, is delivered into the airway by
utilization of the inhalation of the breath of the user (patient)
or of a gas from a pressurized gas cylinder or by some other
device.
The receptacle and administering utensil for the powder preparation
for intratracheobronchial administration are classified into the
following two types according to the dose of the powder preparation
in the receptacle: (i) a type in which the dose of the powder
preparation to be delivered into the airway per one time has
preliminarily been set apart and contained in each receptacle (unit
dose type), and (ii) a type in which a multidose of the powder
preparation is contained in the receptacle, and dose of the powder
preparation is divided up by some means and sent into the airway
every time the preparation is to be used (multidose type).
For the above two types of containing systems, there have been
devised many administering utensils, and as specific examples
thereof, there may be mentioned, e.g., as a unit dose type, the
powder medicine-dispensing device disclosed in Japanese Examined
Patent Publication (Kokoku) No. 63-6024, "Spinhaler" (Registered
Trade Mark), "Rotahaler" (Registered Trade Mark), "Diskbaler"
(Registered Trade Mark) or the like described in "Respiratory Drug
Delivery" edited by P. R. Byron, published by CRC Press, 1990,
p.169, and as a multidose type, "Turbohaler" (Registered Trade
Mark) described on p.169 of the same publication, and the like.
The shapes of receptacles for containing a powder preparation vary
in many ways depending on the above containing systems or the
structure of the administering utensils. As the unit dose type
receptacles, there have hitherto been known, e.g., hard medical
capsules which have been widely used for oral preparations;
disk-shaped molded products which can be charged in a "Diskhaler"
(Registered Trade Mark); and disposable receptacles as proposed in
WO 89/01348 Specification. In addition, as multidose type
receptacles, there have been known the receptacles of such shapes
as can be changed in conformity with the structure of an
administering utensil and a predetermined amount of the content of
the receptacle can be moved from the administering utensil to the
airway. In the present invention, there may be used any of the
receptacles of these shapes. In addition, a receptacle may
constitute a part of an administering utensil. For example, a
receptacle may be cylindrical and, simultaneously, have a structure
such that the receptacles can be removed from its cap and fixed to
an administering utensil by driving a screw.
On the other hand, with respect to the material of a receptacle
containing the powder preparation, even if the present powder
preparation is in the form of an inhalant that is administered into
the airway of the human body, the receptacles are in direct contact
with the powder preparation. Accordingly, as the materials which
have specifically been known as those of the receptacles containing
powder preparations, in consideration of safety and the like, there
may be mentioned, as unit dose type ones, hard gelatin medical
capsules which have widely been used for oral preparations;
aluminium to be molded into a disk-shaped product (see e.g.p.169 of
the above-mentioned publication published by R. Byron); or
plastics, mainly polyolefinic ones such as polyethylene,
polypropylene, and polystyrene, which have been proposed for
disposable receptacles. In addition, as the materials of multidose
type receptacles, there may be mentioned plastics, mainly
polyolefinic ones such as polyethylene, polypropylene, and
polystyrene; aluminium; glass; and the like.
As the powder preparations to be contained in the receptacles made
of various materials, there have been known powder of a medicament
itself alone, which is administered into the airway and deposited
thereto, whereupon the effect of the medicine is exhibited at an
affected part or the preparation is transferred to the whole body
from the affected part and the effect of the medicines exhibited in
the whole body, or mixtures thereof with an appropriate diluent,
e.g. lactose, mannitol, crystallite cellulose and the like.
With respect to such a powder preparation for intratracheobronchial
administration, since it is necessary to reach a target region with
good efficiency and broaden the deposited area at the reached
region, the particle diameter of the powder should be reduced. The
interrelation between the particle diameter of the particles and
the region attained by the preparation has been examined by many
investigators, and though their reported values are not always
consistent with other, it is said that, for example, particles with
a particle diameter larger than 10 .mu.m, but up to about 500
.mu.m, are deposited mainly in the oral cavity and nasal cavity,
particles with a particle diameter above 2 .mu.m and not more than
10 .mu.m are deposited mainly in the trachea, bronchi, and
bronchioles and those having a particle diameter ranging from 0.5
to 2 .mu.m are deposited mainly in the alveoli. (see "The Newest
Biopharmacology" edited by Awazu and Koizumi, published by Nankodo
Publishers, 1991, p.67). The above-mentioned particle size is
applied to a medicament particle alone in the powder preparation
and a particle comprising a medicament, but not to an additive
particle.
According to the technique regarding the above powder preparation
for intratracheobronchial administration, the present inventors
have continued their studies concerning the administration of
powder medicaments into the nasal cavity, bronchi, alveoli or the
like, and been confronted with significant technical problem on the
basis of the fact that the above-mentioned powder preparation is a
powder of fine particles.
That is, it has been found that, while a powder preparation is
contained in the above-mentioned various receptacles and stored, or
while it is charged in administering utensils, the powder
preparation comes in contact with the receptacle owing to
vibration, so that the fine particles of a medicament or fine
particles comprising a medicament become adsorbed and adhered to
the receptacle surfaces. It has been also found that when
administering a medicament into the airway, even if the powder
preparation contained in the receptacles is introduced into the
airway by utilization of a gas pressurized by inhaled breath or
some means, the fine particles adsorbed and adhered to the
receptacle inner surfaces remain in the receptacles as such, so
that the preparation does not reach the airway.
The above problem is quite insignificant, in the case of an oral
preparation, which is to be administered together with the
receptacles containing said preparation, even if the preparation is
adsorbed and adhered to the inner surfaces of the receptacles, but
in the case of a powder preparation for intratracheobronchial
administration, in which the contents alone of the receptacles, not
the receptacles themselves, are administered into the interior of
the body, the amount of delivered content into the body is reduced,
the problem becomes such a serious problem as may give an influence
to the therapeutic effect of the preparation.
As a means of settling the present problem, there have hitherto
been examined usually conceivable methods, such as a method of
making fine particles, e.g. a method of enlarging the density of
the powder preparation, a method of preliminarily adhering and
adsorbing especially fine particles of the powder preparation to
comparatively larger particles in the powder preparation, and the
like, and it has been made clear that some methods are effective
and the present problem has been settled e.g. in the case of
corticosteroid preparation for intranaso-oral spraying
administration. However, even if any of the above-mentioned methods
is employed, depending upon the kind of a medicament, e.g. in
peptides and proteins which exhibit noticeable absorptivity and
adhesion properties to gelatin or plastics, there cannot be avoided
adhesion and adsorption thereof to receptacles. In addition, when
the powder preparation is kept under dried conditions especially
for improvement of the physicochemical stability, it is very
difficult, according to the above method, to prevent the powder
preparation from being adhered and adsorbed to the receptacles.
Therefore, there have been demanded preparations for
intratracheobronchial administration, which do not require
troublesome formation of fine particles, which may be applied to
various medicaments, and which are not adsorbed or adhered to the
internal surfaces of the receptacles. There have been demanded also
preparations for intratracheobronchial administration, which are
not adsorbed or adhered to the inner surfaces of the receptacles,
even under dried conditions.
Incidentally, the technical concept of employing hydroxypropyl
methyl cellulose or the like as the material of receptacles for a
medicament is already known. For example, Japanese Unexamined
Patent Publication No. 61-100519 discloses medical hard capsules
composed essentially of hydroxypropyl methyl cellulose.
On the other hand, it has already been known that various kinds of
unit dose type receptacles and various multidose type receptacles,
including medical hard capsules, have been used as receptacles for
powder preparations for intratracheobronchial administration.
However, until now, it has not been a fact at all that in a powder
preparation for intratracheobronchial administration, there may
occur significant adhesion and/or adsorption of fine particles
comprising a main medicament. It will be understood that to the
present inventor's knowledge, the fact that the above adhesion
adsorption phenomenon can be avoided by use of receptacles composed
of hydroxypropyl methyl cellulose or the like, is novel and cannot
be anticipated at all from the hitherto known literature or the
like.
DISCLOSURE OF INVENTION
The purpose of the present invention is to provide a preparation
for intratracheobronchial administration, which prevents the fine
particles containing medicament from being adhered or adsorbed to
the inner surfaces of the receptacles, so that the amount of the
medicament delivered into the airway is improved.
More specifically, the purpose of the present invention is to
provide a preparation for intratracheobronchial administration,
which does not reduce the amount of the preparation delivered from
receptacles to the airway, even if the preparation is stored under
dry conditions.
In accordance with the present invention, there is provided a
preparation for intratracheobronchial administration, which is
contained in receptacles composed of at least one component
selected from the group consisting of hydroxypropyl methyl
cellulose, methyl cellulose, hydroxypropyl cellulose, starches,
hydroxypropyl starches, and sodium alginate.
The present inventors have repeated their studies for settling the
aforesaid problem, and found the astonishing fact that when a
powder preparation for intratracheobronchial administration is
contained in receptacles composed essentially of a cellulose
derivative or analogue, i.e. a receptacle composed of at least one
component selected from the group consisting of hydroxypropyl
methyl cellulose, methyl cellulose, hydroxypropyl cellulose,
starches, hydroxypropyl starches, and sodium alginate, the
above-mentioned problem can be settled, and finally reached the
present invention.
The adhesion/adsorption to the inner surface of receptacles of the
medicament particles, or the particles comprising medicaments,
contained in a receptacle is related to various factors including,
for example, (1) the physical properties of the receptacle, (2) the
physical properties of the medicament, (3) the physical properties
of the particles of the additives copresent with the medicament
particles and the particles comprising the medicament and (4) the
environmental factors such as humidity is complicated.
It is clearly found as a result of our study heretofore that, when
the medicament particles or particles comprising medicaments only
are finely divided to a particle size necessary for the preparation
for intratracheobronchial administration, i.e., about 500 .mu.m or
less irrespective of the presence of conventional additives, it is
unavoidable irrespective of the physical properties and kinds of
the medicament that the particles are adhered and adsorbed to
conventional receptacles such as gelatin capsules, aluminum disks,
polyethylene receptacles, but are not adhered and adsorbed to the
receptacles according to the present invention. It is not clear
why, to receptacles mainly composed of cellulose derivatives and
analogues such as hydroxypropyl methyl cellulose, methyl cellulose,
hydroxypropyl cellulose, starch, hydroxypropyl starch, sodium
alginate, the above-mentioned particles are not adhered and
adsorbed, due to the facts that the factors are complicated as
mentioned above and the analysis thereof is difficult. However,
these cellulose derivatives and analogues are not statically
charged when contacted with the medicament particles or additive
particles, but it is confirmed by our experiments that the statical
charge occurs in the case of gelatin, polyethylene conventionally
used as the receptacles.
BEST MODE FOR CARRYING OUT THE INVENTION
With respect to the shape of the receptacles used in the present
invention, composed of hydroxypropyl methyl cellulose or the like,
there may be adopted either a type, in which the preparation is
preliminarily divided into each dose to be delivered into the
airway for one time and each dose of the preparation is contained
in each receptacle (unit dose type), or a type, in which the powder
preparations for a plurality of doses are contained in a lump in a
receptacle, such that a dose of powder preparation is divided from
the receptacle and delivered into the airway by some means, every
time the powder preparation is to be used (multidose type). In the
case of a unit dose type, the receptacles may assume the shape of
medical hard capsules, or the shape such that a unit dose is
divided into some pieces and these pieces are contained in a
receptacle on some places of the disk surface of the receptacle
molded into a disk-shaped product. In addition, the receptacle may
be molded into a proper shape in conformity with the shape of an
administering utensil, and also may be a disposable receptacle
integrated with an administering utensil. As a multidose type
receptacle, any suffices if it is adequately molded in conformity
with a multidose type administering utensil and has such a shape as
has a function necessary to be charged in the multidose type
administering utensil, when used, and put to practical use.
Although the proportion of hydroxypropyl methyl cellulose or the
like based on the weight of a receptacle composed of the
hydroxypropyl methyl cellulose or the like is limited by the
hereafter-mentioned production process for the receptacle, it is
preferably 70% by weight or more, and more preferably 80% by weight
or more when a receptacle is composed of two or more kinds of
components, the total weight of these components is desirably
within the above range.
As the compounds to be compounded in a receptacle used in the
present invention, composed of hydroxypropyl methyl cellulose or
the like, there are mentioned plasticizers, thickening agents,
auxiliary agents thereof, coloring matters, and the like.
Specifical examples of these compounds are e.g. polyvinyl alcohol,
polyethylene glycol, sorbitol, mannitol, sucrose, carrageenan,
sodium chloride, potassium chloride, titanium oxide, lake coloring
matter, and the like.
The receptacle is produced by use of at least one compound selected
from the group consisting of hydroxypropyl methyl cellulose, methyl
cellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch,
and sodium alginate. Of these compounds, hydroxypropyl methyl
cellulose is favorable. As hydroxypropyl methyl cellulose to be
used, with respect to the substitution ratio of the cellulose ether
thereof, there is preferred one having a methoxyl group weight
ratio ranging from 15 to 30% and a hydroxypropoxyl group weight
ratio ranging from 3 to 15%, and with respect to the viscosity of
the cellulose ether thereof, there is furthermore desired one
having a viscosity of a 2% aqueous solution at 20.degree. C.,
ranging from 2 to 20 cps. In addition, of usable hydroxypropyl
methyl celluloses, with respect to the substitution ratio of the
cellulose ether thereof, there are furthermore preferred
hydroxypropyl methyl celluloses having a methoxyl group weight
ratio ranging from 19 to 30% and a hydroxypropoxyl group weight
ratio ranging from 4 to 12%. Further, as the hydroxypropyl methyl
cellulose to be used, with respect to its viscosity, more desirable
ones are hydroxymethyl celluloses having a viscosity of a 2%
aqueous solution at 20.degree. C., ranging from 3 to 15 cps.
The receptacle used in the present invention, composed essentially
of hydroxypropyl cellulose, can be prepared in the same manner as a
method for the preparation of hard gelatin capsules which have
often been used as medical capsules. With respect to the details of
the production processes of the capsules, there are disclosed in,
e.g. Japanese Unexamined Patent Publication No. 61-100519, Japanese
Unexamined Patent Publication No. 62-266060, Japanese Unexamined
Patent Publication No. 63-127757, and Japanese Unexamined Patent
Publication No. 3-9755. It will be easily understood that by these
processes, there can be molded all the kinds of unit dose-type and
multidose-type receptacles usable for powder preparations for
intratracheobronchial administration, including medical
capsules.
The powder preparation for intratracheobronchial administration,
used in the present invention, comprises a medicament alone,
revealing a pharmacological effect, or the medicament revealing the
pharmacological effect and additives.
Of the medicaments revealing pharmacological effects, as a
medicament revealing a pharmacological effect at an affected part
in the airway, there are mentioned e.g. steroidal antiinflammatory
drugs such as hydrocortisone, prednisone, prednisolone,
triamcinolone, triamcinolone acetonide, dexametlon, betamethasone,
beclometasone, and beclometasone dipropionate; non-steroidal
antiinflammatory drugs such as acetoaminophenone, phenacetin,
aspirin, aminopyrin, sulpyrine, phenylbutazone, mefenamic acid,
ibufenac, ibuprofen, alclofenac, dichlofenac sodium, indomethacin,
colchicine, and probenecid; enzymatic antiinflammatory drugs such
as chymotrypsin, promelaincerapetase; antihistamines such as
diphenhydramine hydrochloride, chloropheniramine maleate, and
clemastine; antiallergic agents (antitussive, expectorant and
antastimatic drugs) such as disodium cromoglycate, codeine
phosphate, and isoproterenol hydrochloride; antibiotics such as
tetracycline hydrochloride, leucomycin, fradiomycin, penicillin,
and the derivatives thereof, and erythromycin; chemotherapeutants
such as sulfathiazole, and nitrofurazone; local anesthetics such as
benzocaine; vasoconstrictors such as phenylephrine hydrochloride,
tetrahydrozoline hydrochloride, naphazoline nitrate, oxymethazoline
hydrochloride, and tramazoline hydrochloride; cardiac stimulants
such as digitalis, and digoxin; vasolators such as nitroglycerine
and papaverine hydrochloride; antimicrobial agents such as
chlorophexidine hydrochloride, hexyl resorcin, decalinium
hydrochloride, and ethacrydine; enzymes such as lysothium chloride,
and dextranase; anticancer drugs such as furfonracil; erasrase
inhibitors; sympathomimetic drugs such as salbutamol sulfate,
procaterol hydrochloride, and orciprenaline, and phenoterol
hydrobromide; parasympatholytic drugs (cholinergic blocking agents)
such as ipratropium, and furtropium oxalate; sputum-solubilizing
drugs such as acetyl cysteine sodium, and bromhexine;
mucous-lubricating agents such as ambroxol; and the like.
In addition, of the medicaments revealing pharmacological effects,
as the medicaments which are absorbed in the body fluid such as
blood from the airway and reveal pharmacological effects to the
whole body, there are mentioned peptides, proteins, i.e.
polypeptides, having various physiological activities. Of the
polypeptides, those having a molecular weight ranging from 300 to
300,000 are preferable, because these polypeptides are easily
absorbed through the tracheobroncheal mucosa. The molecular weight
of the polypeptides is especially preferably within the range
between 1,000 and 150,000. As specifical examples of polypeptides
having physiological activities, there are mentioned the following:
e.g. peptide hormones such as insulin, angiotensin, vasopressin,
desmopressin, felypressin, protylylene, luteinizing hormone,
corticotropin, prolactin, somatropin, thyrotropin, luteinizing
hormone, calcitonin, kallikrein, parathylin, glucagon, oxitocin,
gastrin, secretin, serum gonadotropin, growth hormone,
erythropoietin, angiotensin, urogastrone, renin, lypomodulin,
calmodulin, and hANP (human Atrial Naturetic Polypeptide), the
chemically modified compounds thereof or components thereof;
biologically active proteins such as interferon, interleukin,
transferrin, histaglobulin, macrocortin, and serum coagulator VIII;
enzyme proteins such as lysozyme, and urokinase.
In addition, of the medicaments revealing pharmacological effects,
as vaccines utilizing the antigen recognition function of the lymph
organization in the airway, there may be mentioned pertussis
vaccine, diphtheric vaccine, tetanus vaccine, influenza vaccine or
lymphocyte increasing factor, fibrous leukocyte agglutinizing
elements, and the like.
Among the medicaments used in the present invention, revealing the
above-mentioned pharmacological effects, it is preferable to use
the medicaments such that the physical loss due to the adhesion and
adsorption thereof to the inner surface of the receptacles is the
substantial loss of the administration amount, namely a small
administration amount of a highly active medicament. The amount of
the adhesion and adsorption to the inner surface of the receptacle
largely depends upon 10 the contact area between the preparation
and the inner surface of the receptacle. For example, when
beclometasone dipropionate powder having a particle size of 5-10
.mu.m is contained in a #2 gelatin capsule, the amount of adhesion
and adsorption is about 10 .mu.g. It should be, however, noted that
the loss of the medicament due to the adhesion and adsorption is
varied depending upon the shapes of the receptacles and the size of
the receptacles based upon a unit dose or a multidose.
Nevertheless, based upon the above-mentioned example of the
beclometasone dipropionate, if it is assumed that the maximum
amount of about 100 .mu.g is lost for each dose, the administration
amount, in which the above-mentioned amount of loss is substantial
loss in the administration amount, is about 2 mg per one dose at
maximum. Accordingly, it is not limited, but the use of the
medicaments having a unit dose in one administration of about 2 mg
or less is preferable. More specifically, the favorable ones are
steroidal antiinflammatory drugs, sympathomimetic drugs,
parasympatholytic drugs, peptides, proteins and vaccines.
Furthermore, the adhesion and adsorption to the receptacle are
especially remarkable in the dried state, and therefore, the
present invention is especially preferable in the case of
medicaments which are dried for the stabilization. Examples of such
medicaments are peptides, proteins, vaccines.
As the additives used together with the medicaments revealing
pharmacological effects in the powder preparation for
intratracheobronchial administration, used in the present
invention, there may be used the additives which have hitherto been
used in powder preparations for intratracheobronchial
administration, or any additive may be used, as long as it is
usable. As such additives, pharmaceutical vehicles are used, and as
concrete examples thereof, there may be mentioned one or a
plurality of members selected from cellulose ethers, water
absorbent and slightly water soluble base materials, sugars, amino
acids and the like.
Cellulose ethers are cellulose derivatives in which a plurality of
hydroxyl groups of cellulose are at least partially etherified, and
examples thereof include e.g. lower alkyl ethers of celluloses,
lower hydroxyalkyl ethers, lower carboxyalkyl ethers, and the like.
The ether groups are not necessarily limited to same kinds, and
e.g. cellulose ethers having 2 or more kinds of ether groups, e.g.
a lower alkyl group and a lower hydroxyl alkyl group in a molecule
are included in the cellulose ethers of the above category. Of
these cellulose ethers, lower alkyl ethers of celluloses or lower
hydroxyalkyl ethers are favorably used. The term, "lower alkyl"
herein referred to means an alkyl group with 5 or less carbon
atoms, preferably 3 or less carbon atoms.
As the above-mentioned cellulose ethers, there may be mentioned
methyl cellulose, ethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl
cellulose, carboxymethylhydroxy cellulose, hydroxypropyl methyl
cellulose, and the like. Among them, there is preferably used
especially methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose or hydroxypropyl methyl cellulose.
As the cellulose ethers, e.g. those having a viscosity of the 2% by
weight aqueous solution thereof at 20.degree. C., ranging from 3 to
100,000 centipoises, more preferably from 3 to 10,000 centipoises,
especially preferably from 6 to 6,000 centipoises are preferably
used.
As the cellulose ethers, e.g. those having an ether substitution
degree ranging from 0.1 to 6.0, especially from 0.4 to 4.6 are
preferably used. The term, "ether substitution degree", herein
referred to means the average number of ether groups per glucose
unit composing the cellulose, with regard to three hydroxyl groups
of said one unit.
As the water absorbable and slightly water soluble bases, there may
be mentioned e.g. water absorbable and slightly water soluble
celluloses such as crystalline cellulose, .alpha.-cellulose, and
cross-linked carboxymethyl cellulose sodium; water absorbable and
slightly water soluble starches such as hydroxypropyl starch,
carboxymethyl starch, cross-linked starch, amylose, amylopectin,
and pectin; water absorbable and slightly water soluble proteins
such as gelatin, casein, and casein sodium; water absorbable and
slightly water soluble gums such as gum Arabic, gum tragacanth, and
glucomannan; cross-linked vinyl polymers such as polyvinyl
polypyrrolidone, cross-linked polyacrylic acid and the salts
thereof, cross-linked polyvinyl alcohol, and polyhydroxymethyl
methacrylate. Of these bases, water absorbable and slightly water
soluble celluloses are preferable, and especially crystalline
cellulose is favorable.
As the sugars, there may be mentioned glucose, annitol, lactose,
fructose, dextran, and the like.
As the amino acids, there may be mentioned glycine, alanine and the
like. In addition, besides these pharmaceutical vehicles, there are
added, if necessary, a dispersion auxiliary agent, lubricant,
stabilizer, and the like.
Now, the above-mentioned additives and the medicaments exhibiting
the pharmacological effects may be present in the separate
particles in the preparations or may form the same particles
together. In the former case, the additives and the medicaments can
be mixed, for example, mechanically. In the latter case, the
additives and the medicament may be dispersed or dissolved in a
solvent or solvents, followed by, for example, spray drying to form
the preparation.
Now, the preparation for intratracheobronchial administration from
the above-mentioned receptacle and powder preparation (comprising a
medicament alone or the medicament and additives) is described. The
production process thereof varies according to the aimed region in
the airway, to which the medicament is to be delivered. That is, as
described above, it is said that the region in the airway, to which
a medicament can be delivered, is determined in accordance with the
particle diameter of a preparation; e.g. particles with a particle
diameter of more than about 10 .mu.m, but not more than about 500
.mu.m are deposited mainly in the oral cavity and nasal cavity,
those having a particle diameter more than 2 .mu.m but not more
than 10 .mu.m are deposited mainly in the trachea, bronchi, and
bronchiole, and those having a particle diameter ranging from 0.5
to 2 .mu.m are deposited mainly in the alveoli. Therefore, by
adjusting the particle diameter of the powder preparation, it is
possible to efficiently deliver the medicament to the targeted
region. Perferably, at least 80 percent by weight of the particles
in the powder preparation will have a diameter ranging from about
0.5 to 149 .mu.m.
First, in order to deliver the medicament in the oral cavity and
nasal cavity, it suffices, if the particle diameter of the powder
preparation to be contained in the receptacles of the present
invention is adjusted to a value greater than 10 .mu.m, but not
more than 500 .mu.m. Among such powder preparations, as an example
of preparation for topical application, there may be mentioned e.g.
a curative medicine for nasal allergy, which is obtained by mixing
e.g. beclometasone dipropionate, a steroidal antiinflammatory drug,
having a particle diameter of more than 10 .mu.m, but not more than
500 .mu.m and hydroxypropyl cellulose, an additive having a
particle diameter of more than 10 .mu.m, but not more than 500
.mu.m by a mixer. In the above case, in order to maintain the
effect of the medicament for a long time, as the additives to be
compounded into the preparation together with the main ingredient
of the preparation, cellulose esters such as the exemplified
hydroxypropyl cellulose are preferable. As other drugs for local
application, there may be mentioned the other steroidal
antiinflammatory drugs, non-steroidal antiinflammatory drugs,
enzymatic antiphlogistics, antihistamic agents, antiallergic
agents, vasoconstrictors, and the like. In addition, among the same
kinds of powder preparations as above, as medicines for whole body,
there are mentioned, e.g. transnasal preparations, the main
medicament of which is proceeded to the vascular flow through the
nasal mucosa and exhibits systemic action, and these transnasal
preparations are prepared by mixing e.g. calcitonin with a particle
size larger than 10 .mu.m, but not more than 500 .mu.m, e.g. salmon
calcitonin with microcrystalline cellulose with a particle size
larger than 10 .mu.m, but not more than 500 .mu.m by a mixer. In
the above case, in order to obtain rapid onset of medical effect
and good absorption, as the additives to be compounded into the
preparation together with the main medicament, there are preferred
the water absorbent and slightly water soluble bases as exemplified
above. As the other medicaments for whole body, there may be
mentioned peptides other than calcitonin, polypeptides such as
proteins, vaccines, and the like.
Next, in order to deliver the medicament into the trachea, bronchi,
bronchioles, and alveoli, it suffices, if the particle diameter of
the powder preparation to be contained in the receptacles of the
present invention is adjusted within the range between 10 .mu.m and
0.5 .mu.m. In the above case, all the particles do not necessarily
need to have a particle diameter within the above range, but the
more of whole amount of the particles having a particle diameter
within the above range, the more the amount of the particles
delivered into the trachea, bronchi, bronchioles, and alveoli.
Of these powder preparations, as medicament for local effect, there
may be mentioned e.g. an antiasthmatic agent, which is prepared by
making e.g. beclometasone dipropionate, a steroidal
antiinflammatory drugs, and hydroxypropyl cellulose, an additive,
and spray drying the mixture as fine particles having a particle
diameter ranging from 10 to 0.5 .mu.m. As other medicaments for
local action, there may be mentioned the other steroidal
antiinflammatory drugs, non-steroidal antiinflammatory drugs,
enzymatic antiinflammatory drugs, antiallergic agents, antihistamic
agents, elastase inhibitors, sympathomimetic drugs,
parasympatholytic drugs, keratolytic drugs, mucosa swelling agents,
and the like.
In addition, of the same kinds of preparations as above, as
medicament for systemic effect, there may be mentioned a
transpulmonary preparation, the main medicament of which proceeds
into the vascular flow through the alveolo mucosas and exhibits
systemic effect, which is obtained by making e.g. insulin and
dextrose into fine particles having a particle diameter ranging
from 10 to 0.5 .mu.m. As other medicaments for whole body effect,
there may be mentioned other peptides, polypeptides such as
proteins, and the like. As the additives used in these powder
preparations to be delivered into the trachea, bronchi,
bronchioles, and alveoli, slightly stimulative and water soluble
ones are desirable, and e.g. sugars, amino acids, and water soluble
cellulose ethers are preferable.
The preparation of the present invention is administered into the
respiratory tract through the nasal cavity or oral cavity, and the
power source necessary for the preparation of the present
invention, contained in the receptacles, to be introduced into the
airway through the nasal and oral cavities, may be either the
breathed air (inhalation) of a patient himself or a power source
other than the breathed air of the patient, e.g. a balloon method
or the like.
The powder preparation for intratracheobronchial administration,
used in the present invention, is contained in the aforesaid
receptacles used in the present invention, composed of the
components such as hydroxypropyl methyl cellulose or the like, and
thereby obtained in the form of a preparation. The shape of the
receptacles is selected in conformity with the structure of the
administering utensil, and therefore, the structure of the
administering utensil is significant.
The structure of the administering utensil used when administering
the powder preparation of the present invention is subjected to no
restriction, as a general rule, and any administering utensil may
be used, as long as it is the administering utensil (administering
device) which has hitherto been used or proposed. As a unit dose
type administering utensil, there may be mentioned e.g. the powder
preparation-administering device (Japanese Examined Patent
Publication No. 63-6024) corresponding to the medical hard capsule,
"Spinhaler" (Registered Trade Mark), "Rotahaler" (Registered Trade
Mark), "Diskhaler" (Registered Trade Mark) and the like.
In addition, as administering utensil corresponding to the
multidose type receptacles, there may be mentioned e.g.
"Turbohaler" (Registered Trade Mark), and the like.
Industrial Applicability
As explained above, according to the present invention, when a
preparation for intratracheobronchial administration comprising a
powder preparation for intratracheobronchial administration
contained in receptacles composed of hydroxypropyl methyl cellulose
or the like is administered into the airway by such an
administering utensil as described above, the powder preparation is
adhered or adsorbed to the receptacle inner surfaces in a less
amount than the case where a powder preparation contained in
conventional receptacles is administered into the airway by such an
administering utensil as above, so that the amount of the present
powder preparation actually delivered into the airway is larger,
which fact is very meaningful in view of the curative effect.
EXAMPLES
The present invention will now be further explained in detail with
reference to the Examples, but it is to be noted that the present
invention is not limited thereto.
Examples 1 to 16, Control Examples 1 to 64
The following experiments were performed for the purpose of
clarifying that a powder preparation for intratracheobronchial
administration exhibits only slight adhesiveness/adsorptiveness to
receptacles composed essentially of hydroxypropyl methyl
cellulose.
(1) Production of a measuring box for the amount of the powder
preparation adhered/adsorbed to various receptacle materials:
A box having one square base with a side length of 2 cm and a
height of 1 cm, the other base being opened, was made of a
cardboard, and a thin filmy material described in the following
item (2) was stuck to the 5 faces confronting the inside of the box
(4 lateral faces and one base) with "Alon alpha" (produced by Toa
Gosei Kagaku).
(2) Preparation of the thin filmy material to be stuck to the inner
faces of the measuring box for adhered/adsorbed amount:
As described in the following, there were prepared five kinds of
materials including the material composed essentially of
hydroxypropyl methyl cellulose.
Material A: A thin film with a thickness of 0.1 mm, consisting of
93 parts by weight of hydroxypropyl methyl cellulose (produced by
Shinetsu Kagaku, trade name: "TC-5R": methoxyl group: 28 to 30% by
weight, hydroxypropoxyl group: 7 to 12% by weight, viscosity of a
2% aqueous solution at 20.degree. C.: 6 cps), 1 part by weight of
carrageenan (produced by Wako Junyaku), 1 part by weight of
potassium chloride (produced by Wako Junyaku), and 5 parts by
weight of water. (A solution obtained by dissolving above
substances in an excessive amount of water was spread on a flat
plate, and dried so as to be formed into a uniform filmy
product.)
Material B: A thin film with a thickness of 0.1 mm, consisting of
95 parts by weight of gelatin (produced by Wako Junyaku) and 5
parts by weight of water. (A solution obtained by dissolving the
gelatin in an excessive amount of water was spread on a flat plate,
and dried so as to be formed into a uniform filmy product.)
Material C: Polypropylene sheet (A sheet produced by Nikko was used
as such.)
Material D: Aluminium foil (A Nippaku foil was used as such.)
Material E: Ordinary thin sheet glass.
(3) Preparation of a powder preparation for intratracheobronchial
administration, comprising a medicament:
The medicaments, bases, and lubricants described in Table 1 were
mix-prepared by the methods described in Table 1, respectively, so
that powder preparations for intratracheobronchial administration
were prepared. The particle size distributions of the prepared
powder preparations are also set forth in Table 1.
(4) Method of determining the amount of the adhered and adsorbed
medicament:
Each 100 mg of the powder preparations for intratracheobronchial
administration, prepared in the above (3) were introduced into the
measuring boxes described in (1), which had been lined,
respectively, with the materials described in (2), and each of the
boxes was shaked right and left by a shaker, so that each powder
preparation was brought into contact with each material. During the
shaking operation, the top open face was covered in order to
prevent the content of the box from being scattered. (These
experiments were performed under the conditions of 25.degree.
C./40% RH.) After the shaking operation had been completed, the lid
was removed and the contents were taken out. The powder
preparations were, respectively, discharged by tapping the box with
a spatula, or by other means, until the powder preparation could
not be recognized with naked eyes on the base and lateral faces of
the box. The discharged powder preparations were collected and the
medicament contained therein was measured by high speed liquid
chromatography, whereupon the amount of powder preparation adhered
or adsorbed in the inner faces of the box was calculated on the
basis of the amount of the powder preparation initially introduced
in the box. The results of Examples 1 to 16, with variation of the
combinations of the receptacle materials and powder preparations,
are set forth in Table 2, and the results of Contrast Examples 1 to
64, with variation of the combinations of the conventional
receptacle materials and powder preparations are set forth in Table
3.
TABLE 1
__________________________________________________________________________
Powder Prepa- Prep. ration No. Medicament Base Lubricant method
Remarks
__________________________________________________________________________
1 Salmon Microcrystalline Magnesium a Preparation calcitonin.sup.1)
cellulose.sup.10) stearate.sup.15) for nasal (100 I.U.) cavity 2
Salmon Cross-linked Magnesium a Preparation calcitonin.sup.1)
starch.sup.11) stearate.sup.15) for nasal (100 I.U.) cavity 3
Insulin.sup.2) Microcrystalline Magnesium a Preparation (5 I.U.)
cellulose stearate.sup.15) for nasal cavity 4 Insulin.sup.2)
Hydroxypropyl Magnesium b Inhalant (5 I.U.) cellulose.sup.12)
stearate.sup.15) 5 Insulin.sup.2) Hydroxypropyl Magnesium c
Inhalant (5 I.U.) cellulose.sup.12) stearate.sup.15) 6 LHRH.sup.3)
Microcrystalline Magnesium a Preparation (400 .mu.g) cellulose
stearate.sup.15) for nasal cavity 7 LHRH.sup.3) Lactose.sup.13)
Magnesium b Inhalant (400 .mu.g) stearate.sup.15) 8 LHRH.sup.3)
Hydroxypropyl Magnesium c Inhalant (400 .mu.g) cellulose
stearate.sup.15) 9 Beclometasone Hydroxypropyl Magnesium a
Preparation dipropionate.sup.4) cellulose stearate.sup.15) for
nasal (400 .mu.g) cavity 10 Beclometasone Lactose Magnesium b
Inhalant dipropionate.sup.4) stearate.sup.15) (400 .mu.g) 11
Beclometasone Hydroxypropyl Magnesium c Inhalant
dipropionate.sup.4) cellulose stearate.sup.15) (400 .mu.g) 12
Salbutamol Hydroxypropyl Magnesium b Inhalant sulfate.sup.5)
cellulose stearate.sup.15) (100 .mu.g) 13 Ipratropium Hydroxypropyl
Magnesium c Inhalant bromide.sup.6) cellulose stearate.sup.15) (40
.mu.g) 14 Triamcinolone Hydroxypropyl Magnesium a Preparation
acetonide.sup.7) methyl stearate.sup.15) for nasal (400 .mu.g)
cellulose.sup.l4) cavity 15 Procaterol Hydroxypropyl Magnesium b
Inhalant hydrochloride.sup.8) methyl stearate.sup.15) (50 .mu.g)
cellulose.sup.l4) 16 Fenoterol Hydroxypropyl Magnesium c Inhalant
hydrobromide.sup.9) cellulose stearate.sup.15) (200 .mu.g)
__________________________________________________________________________
.sup.1) produced by Sigma Inc. .sup.2) produced by Sigma Inc.
.sup.3) produced by Peptide Research Institute .sup.4) produced by
Sigma Inc. .sup.5) produced by Sigma Inc. .sup.6) produced by Sigma
Inc. .sup.7) produced by Sigma Inc. .sup.8) produced by Sigma Inc.
.sup.9) produced by Sigma Inc. .sup.10) "Apicel PH101" produced by
Asahi Kasei .sup.11) produced by Nichiden Kagaku .sup.12) "HPCH"
produced by Nippon Soda Inc. .sup.13) produced by Megle .sup.14)
"TC5R" produced by Shinetsu Kagaku
In Table 1, the content in 30 mg of each powder preparation was
shown in each pair of parentheses. In addition, the content of
magnesium stearate was 0.5% by weight of each powder preparation.
Mix-preparation was effected in the following manner.
a) To a predetermined amount of the medicament having a particle
diameter of 46-149 .mu.m, there was added a base having 90% by
weight or more of particles with a particle diameter ranging from
46-149 .mu.m, followed by mixing in a small-sized V-type mixer
until the mixture becomes uniform and finally 0.5% of magnesium
stearate was mixed to the obtained mixture, whereby a homogeneous
powder preparation for intranasal administration was obtained.
b) To a predetermined amount of the medicament having a particle
diameter of 0.5-10 .mu.m, there was added a base having 90% or more
of particles with a particle diameter of 46-149 .mu.m, followed by
mixing in a small-sized v-type mixer until the mixture becomes
uniform, and finally 0.5% of magnesium stearate was mixed to the
obtained mixture, whereby a homogeneous powder preparation for
internasal administration was obtained.
c) A predetermined amount of a medicament and base were dissolved
into a solvent composed essentially of water (ethanol was added, if
necessary), and the obtained solution was spray dried to prepare a
powder of minute particles, whereafter 0.5% of magnesium stearate
was added to the obtained powder, so that a powder preparation
(inhalant) for intratracheobronchial administration was
obtained.
The particle size distribution of the powder preparations obtained
by the above-mentioned preparing method c) was 0.5 to 10 .mu.m for
80% or more thereof. The results obtained by use of a laser type
particle size measuring machine (JEOL/SYMPATEC; HEROS &
ROODS).
TABLE 2 ______________________________________ Receptacle Powder
Adhering/Adsorbing Example Material Preparation Rate (%)
______________________________________ 1 A 1 2 2 A 2 3 3 A 3 3 4 A
4 7 5 A 5 8 6 A 6 4 7 A 7 6 8 A 8 7 9 A 9 2 10 A 10 4 11 A 11 7 12
A 12 2 13 A 13 3 14 A 14 3 15 A 15 4 16 A 16 5
______________________________________
TABLE 3 ______________________________________ Receptacle Powder
Adhering/Adsorbing Example Material Preparation Rate (%)
______________________________________ 1 B 1 15 2 " 2 18 3 " 3 20 4
" 4 23 5 " 5 26 6 " 6 17 7 " 7 19 8 " 8 25 9 " 9 19 10 " 10 18 11 "
11 27 12 " 12 20 13 " 13 16 14 " 14 19 15 " 15 20 16 " 16 24 17 C 1
31 18 " 2 28 19 " 3 34 20 " 4 45 21 " 5 49 22 " 6 30 23 " 7 35 24 "
8 37 25 " 9 29 26 " 10 26 27 " 11 46 28 " 12 36 29 " 13 33 30 " 14
29 31 " 15 32 32 " 16 43 33 D 1 18 34 " 2 19 35 " 3 21 36 " 4 23 37
" 5 30 38 " 6 20 39 " 7 20 40 " 8 28 41 " 9 16 42 " 10 18 43 " 11
21 44 " 12 15 45 " 13 17 46 " 14 19 47 " 15 20 48 " 16 22 49 E 1 19
50 " 2 18 51 " 3 18 52 " 4 25 53 " 5 27 54 " 6 16 55 " 7 17 56 " 8
21 57 " 9 15 58 " 10 14 59 " 11 28 60 " 12 13 61 " 13 14 62 " 14 15
63 " 15 16 64 " 16 23 ______________________________________
From Table 2 and Table 3, it can be seen that the
adhesiveness/adsorptiveness of the powder preparation for
intratracheobronchial administration to receptacles composed
essentially of hydroxypropyl methyl cellulose is less than that to
receptacles made of gelatin, polypropylene, aluminium foil or
glass.
Examples 17-21, Control Examples 65-69
The powder preparations 1, 3, 6, 9 and 14 described in the above
Table 1 were filled up into medical hard capsules composed
essentially of hydroxypropyl methyl cellulose (composition: 93
parts by weight of hydroxypropyl methyl cellulose, "TC-5R" produced
by Shinetsu Kagaku; 1 part by weight of carrageenan; 1 part by
weight of potassium chloride; 5 parts by weight of water), in an
amount of 30 mg, respectively, and, after storing at 25.degree. C.
and 55% RH for 2 weeks, the powder preparations were sprayed by a
powder preparation-administering device (Japanese Examined Patent
Publication No. 63-6024) until the powder preparation could not be
recognized with naked eyes, following which the above-mentioned
capsules were taken out and the medicament remained in the capsule
inner faces was subjected to measurement by HPLC, whereby the
adhesion-adsorption ratio of the powder preparation to the capsule
inner faces was calculated. (Examples 17-21).
In addition, the powder preparations 1, 3, 6, 9, and 14 also
described in the above Table 1 were, respectively, filled up into
each of medical capsules composed essentially of gelatin
(composition: 95 parts of gelatin and 5 parts by weight of water)
in an amount of 30 mg, whereupon the same experiments as described
in Examples 17 to 21 were conducted. (Control Examples 65-69).
The results are set forth in Table 4.
TABLE 4 ______________________________________ Rate of
Adhesion/Adsorption (%) 25.degree. C./55% RH Drying Conditions
______________________________________ Example 17 2 4 18 4 5 19 3 5
20 5 7 21 5 7 Control Example 65 9 25 66 13 43 67 10 39 68 19 47 69
25 46 ______________________________________
It may be seen from Table 4 that the proportion of the powder
preparation for intratracheobronchial administration remained in
the insides of capsules, when the powder preparation filled in the
capsules composed essentially of hydroxypropyl methyl cellulose is
sprayed from a powder preparation-administering device, is less
than the proportion of the preparation remained when the
preparation is filled in gelatin capsules and simultaneously
sprayed, and also that the amounts of the adhesion/adsorption are
not affected by the drying. Note that there are some gelatin
capsules causing cracks during drying.
Examples 22, 23, and Contrast Examples 70 and 71
The powder preparations 4 and 11 described in the above Table 1
were filled up in medical hard capsules composed essentially of
hydroxypropyl methyl cellulose in an amount of 5 mg, respectively,
like Examples 17 to 21, and holes were made in the capsules by use
of a powder preparation-administering device in the same way as
described in the above Examples 17 to 21, following which a suction
pump was connected to the device and the contents of the capsules
were sucked at a rate of 60 liter/min by this suction pump,
whereafter the amount of main medicament remained on the capsule
inner faces was determined by the similar way, so that the rate of
the medicament adhered to the capsule inner faces was calculated
(Examples 22 and 23).
The same experiments were performed also with respect to the same
powder preparations 4 and 11 filled up in gelatin capsules, whereby
the rates of the powder preparations adhered to the capsule inner
faces were calculated, respectively. (Contrast Examples 70 and
71).
The results are set forth in Table 5.
TABLE 5 ______________________________________ Rate of
Adhesion/Adsorption ______________________________________ Example
22 5 Example 23 4 Contrast Example 70 18 Contrast Example 71 23
______________________________________
It can be seen from Table 5 that the proportion of the contents of
a powder preparation for intratracheobronchial administration,
remained in the insides of capsules, when the contents of the
preparation filled up in capsules composed essentially of
hydroxypropyl methyl cellulose are sucked in the same manner as
human inhalation is less than the proportion of the preparation
remained in gelatin capsules when the contents of the preparation
filled up in the gelatin capsules are sucked in the same way as
above.
Examples 24 to 28
Thin film-like materials, each composed of the following materials
F, G, H, I, and J, respectively, were prepared, in the same way as
in Examples 1 to 16.
Material F: A thin film with a thickness of 0.1 mm consisting of 95
parts by weight of methyl cellulose ("Metholose SM 15" produced by
Shinetsu Kagaku) and 5 parts by weight of water (A solution
obtained by dissolving the methyl cellulose with an excessive
amount of cooled water was spread on a flat plate, whereafter it
was dried so as to form a uniform thin film.)
Material G: A thin film with a thickness of 0.1 mm, consisting of
95 parts by weight of hydroxypropyl cellulose ("Nisso HPC-M") and 5
parts by weight of water (A solution obtained by dissolving the
hydroxypropyl cellulose with an excessive amount of cooled water
was spread on a flat plate, whereafter it was dried so as to be
formed into a uniform thin film.)
Material H: A thin film with a thickness of 0.1 nun, consisting of
95 parts by weight of starch (Indian corn starch produced by Nippon
Shokuhin Kako [Japan Food Processing Industries Co., Ltd.] and 5
parts by weight of water (The starch was solubilized with boiling
water, whereafter the solubilized starch was spread on a flat
plate, following which it was dried so as to form a uniform thin
film.)
Material I: A thin film with a thickness of 0.1 mm, consisting of
95 parts by weight of hydroxypropyl starch ("HPS 101 (W)" produced
by Freund Industries Inc.) and 5 parts by weight of water (The
hydroxypropyl starch was solubilized with boiling water, whereafter
the solubilized starch was spread on a flat plate, following which
it was dried so as to form a uniform thin film.)
Material J: A thin film with a thickness of 0.1 mm, consisting of
95 parts by weight of sodium alginate (produced by Kimitsu Chemical
Inc.) and 5 parts by weight of water (A solution obtained by
dissolving the sodium alginate in cool water was spread on a flat
plate, following which it was dried to form a uniform thin
film.)
For these materials F to J, and the powder preparation 1 of
Examples 1 to 16, the same experiments as in Examples 1 to 16 were
performed, whereby the adhesion/adsorption rates of the powder
preparation 1 to the materials F to J were determined,
respectively. The results are set forth in Table 6.
TABLE 6 ______________________________________ Receptacle Powder
Adhesion/Adsorption Example Material Preparation Rate (%)
______________________________________ 24 F 1 4 25 G 1 2 26 H 1 3
27 I 1 3 28 J 1 3 ______________________________________
It can be seen from Table 6 that the adhesion/adsorption rates of a
powder preparation for intratracheobronchial administration, to the
receptacles, composed essentially of methyl cellulose,
hydroxypropyl cellulose, starch, hydroxypropyl starch, and sodium
alginate, respectively, are low in the same degree as the
adhesion/adsorption rates of the same preparation to a receptacle
composed essentially of hydroxypropyl methyl cellulose.
* * * * *